DNase I acutely increases cystic fibrosis sputum elastase activity and its potential to induce lung hemorrhage in mice.
The potential of DNase I to increase cystic fibrosis sputum elastase activity and lung damage was evaluated. Sputum from CF patients induced little lung hemorrhage when instilled intranasally in C57BL/6 mice. However, sputum treated in vitro by the addition of 1 mg/ml bovine DNase I showed increased neutrophil elastase activity (7.97 +/- 1.56 versus 3.91 +/- 0.62 microM, p < 0.01) and induced marked lung hemorrhage in mice (bronchoalveolar lavage fluid hemoglobin = 192.8 +/- 40.7 versus 44.5 +/- 12.0 microg/ml, p < 0.01). These effects were not observed with DNase I alone in phosphate buffer and were suppressed by the human neutrophil elastase inhibitor methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSAAPV-CMK). In vivo administration of 2.5 mg aerosolized recombinant human DNase I to patients with CF resulted in a 2.2-fold increase of sputum elastase activity within 1 h of treatment. Elastase levels returned to pre-rhDNase therapy levels 24 h after aerosol treatment. Sputum collected 1 h after rhDNase on 4 separate days from two of six patients in which elastase levels were highest, induced lung hemorrhage when instilled intranasally in mice. We conclude that DNase I therapy of patients with cystic fibrosis can acutely increase the elastase activity of sputum and also its potential to induce hemorrhage in the murine lung.
Cantin
A M
AM
Unité de Recherche Pulmonaire, Centre Universitaire de Santé de l'Estrie, Fluerimont, Quebec, Canada. a.cantin@courrier.usherb.ca
D000328:Adult; D000818:Animals; D002417:Cattle; D003550:Cystic Fibrosis / Q000201:enzymology*; D003850:Deoxyribonuclease I / Q000494:pharmacology*; D005260:Female; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism / Q000502:physiology*; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins; D013183:Sputum / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology
D011994:Recombinant Proteins; D003850:Deoxyribonuclease I; D019272:Leukocyte Elastase